Good afternoon, everyone. Thank you for joining us. Really pleased to have Sam Kulkarni, CEO of CRISPR Therapeutics, here with us. Sam, perhaps to start here, you have a couple of verticals. You have cancer, ex-vivo non-cancer, regenerative medicine, and in-vivo verticals. Can you discuss how you're prioritizing across the pipeline in addition to capital allocation and how you leverage R&D across these separate verticals? Yeah, thank you for having us here, Salveen. As a company, we've been shaping our portfolio over the last nine years as a company's journey. There are a couple of different elements that went into where we ended up today in the portfolio. One is the key question of where can CRISPR be the most transformative and powerful from a technology standpoint? Two is, what are the diseases we want to impact? Thinking has evolved. In the early days, people said, oh, CRISPR is all about rare diseases. Here are the mutations we know about. Here's hundreds of rare diseases we can impact. But if I project forward, I think CRISPR is going to have equal impact on rare diseases and common diseases. So we made that bet to say we're going to have a mix of both because we're not going to say these are the diseases we want to play in. It's going to be, where can we have the most impact based on the technology we have? The second is the fundamental bets to say CRISPR, obviously sickle cell and thalassemia is one franchise, and it was very clear that that was the best place for us to start off with. And we have now approved drug with CASGEVY. But outside of that, we parlayed competencies. We knew cell handling, we knew cell technology. So we said we're going to go into allo-CAR-T or CAR-T in general because we can use CRISPR to make all these modifications to make the best-in-class CAR-T to impact cancer. It's going to bring a new frontier in the fight against cancer that's been ongoing for the last 60 years now, ever since we declared the modern war on cancer. Then we said regenerative medicine. This is an area that still, I think, is underinvested from a venture standpoint and everything else because if you're able to replace organ systems, that transforms how we think about not just certain diseases, but even longevity. I went to this longevity conference where people were saying if your brain is intact and you can replace all the organs, that just you think about longevity very differently than you think about it today with telomeres and everything else. And then we have this other vertical, which is in vivo gene editing, which was we weren't the first. There was enabled by another company. But now I think we could be sort of the biggest mover in the space because we're going to have many, many programs in the in-vivo setting, not just for liver editing, but for other organs as well. So that's the logic of the different franchises. And then the orthogonal axis is the disease areas. And that's how we think about our entire portfolio from a risk-reward standpoint. All that said, I think the bar for us to enter any of to call something a program is very high. It has to be something that really changes the disease landscape. You know. As you spoke about, you talked about CRISPR being a very important tool here that you can use in the future to treat all these diseases. But there's been so much innovation in gene editing. And so how are you adapting to this dynamic landscape to think about a sustainable pipeline? Absolutely. I think one of the most important considerations for us is that we don't get disrupted. We are the leaders in the gene editing space, and we have been. But we want to make sure that we're looking at every improvement that's coming out there. And this is similar to what happened with antibodies in the '80s and '90s, late '80s, early '90s. And in fact, we were seeing antibody improvement even today. People are creating all sorts of bispecifics to give it sort of a new wind in the sales of biologics. But ultimately, value is going to accrue to the ones that use the improvements to make good drugs. You can't just say I'm doing improvements for improvement's sake. So it's innovation with a purpose. But let me tell you what we're doing at CRISPR. We have established a group called CRISPR-X that is dedicated to all sorts of next-gen editing. The notion of CRISPR has changed. There's an interesting experiment we did. There was an artist who had done a rendering of CRISPR for us when we started the company. This was like a graffiti art. The notion of CRISPR was molecular scissors. So it was like the art incorporated scissors. Today, the notion of CRISPR is a cargo van that is taking effector proteins to a particular site on the genome. So with the very premise is still the same with the 20 base pair or 19 base pair, whatever you want to call it, sequence that's very specific in the genome, you can bring any effector protein, whether it's a base editor, whether it's a reverse transcriptase, whether it's a ligase, a recombinase, or whatever else. So you take the entire toolbox of effector proteins, and you can bring them site-specifically to the genome. So that opens up a lot of possibilities. But you have to be very practical and thoughtful about what you're going to apply because if you just start chasing technologies, you're never going to actually have a program that you're going to move forward. So for each disease, what we're looking at to say is, for this disease, what is the best way to address that disease? And we're going to incorporate all these technologies that are available to us. And we're doing a lot of it ourselves. We're developing newer technologies ourselves in addition to incorporating what others have developed. Could you just touch on delivery technology in the context here and your strategy around optimizing for the different tissue targets? Yeah. So the state of the art where we are right now, if you go back seven years and say, what were we thinking then versus where are we now? I think the world was a lot more bullish on viruses, delivery vehicles versus LNPs or polymers or any other modalities. And what's changed now is what we realized is LNPs may be a better way to go because of two reasons. One is, generally, they're degradable and they're safe. Once you're done with the delivery, they're gone. So you don't have viruses hanging around. Second is, it's much more titratable than you are with viruses. So there's variability than what you may get with AAVs or lentivirus. And lentivirus have their own set of issues. And the third point is the regulators feel a lot more comfortable with delivery vehicles like LNPs because it's easier to handicap versus viruses. And so with that sort of backdrop, we're investing quite a bit in LNP, not just for the liver, but for other organ systems as well. We just showed data at ASGCT for delivery using LNPs to the eye, which wasn't where we were. The field was 5, 6 years ago. Everyone was thinking AAV is the way to go for the eye. But now you can get delivery with LNPs. So it's been a dramatic shift. That said, there's still challenges. It's not solved outside the liver by any means at this point. People will say, oh, here's editing in bone marrow with LNPs and look at the great data. Yes, but at very high doses without having shown durability yet. So you still have ways to work these out where you're targeting only a certain organ and detargeting the liver, for instance, detargeting the spleen. People have shown now LNP data for the lung. People are showing LNP data for the eye, as I said, and kidneys. I think there's more work to do. But when that gets solved for other organ systems, you're going to see another wave of applications with gene editing because you're opening up a whole new opportunity set. Let's start here with your commercial portfolio and talk about Casgevy, which is partnered with Vertex here, about the launch to date and maybe walk us through how physician and patient feedback and uptake overall has been. First of all, I'll say that we're very pleased to be partnered with Vertex on this important launch. This launch is important not just for us as companies, but in fact, when we were at the ARM meeting, that was the most talked about. So So then some of the TTR or DMD that people are looking at as investors because CASGEVY, for many reasons, I think the unmet need is so high for these patients. They have no other options. Here's a curative option. Can we, as a system, work out how a medicine like CASGEVY can also be economically very fruitful? And for that, I think the launch is a nuanced launch. It's different from what people typically think of as the ways to handicap launch or look at launches. And I think what we're very pleased with is there is significant demand. And again, Vertex is going to do all the sort of guidance to the street on how to think about the launch and what the parameters are and how they're going to disclose self-selections, for instance, or revenues. But what I'll say is, from my own experience, we're deeply involved with a lot of investigators in the community. The demand is there. Patients are saying, this can change my life. I want to avail this technology. What surprised me is that the system has been very supportive from a reimbursement standpoint, more so than what I'd anticipated eight years ago, for instance. The demand is global. It's not just the U.S. And when you have a therapy like it's available, hospitals figure it out. There are a lot of questions and, I would say, misgivings about whether hospitals are going to have enough beds or are they going to have enough staff to deal with the autologous therapy like this. They figured it out in the Yescarta case. Now they're going to figure it out in the Casgevy case because when there's an available treatment, the system finds solutions around it. So all the, I would say, the fundamentals are pointing in the right direction. But we have to show you how that's all working out. Vertex, as I said, will disclose this information on cell collections, et cetera, every quarter. I feel very good about the Casgevy launch. I think it's going to be an unusual launch in the sense that it's going to be a growth driver for a very long time to come. Typically, you've seen with pharma launches, you get the early pickup, and then they flatten out. Here, they're going to keep growing for a very, very long time to come. Have there been any sticking points on reimbursement and eligibility? Without going into specifics, just in the world of rare disease reimbursement these days, I think what you're seeing is on the U.S. side, there was a bit of this reaction to certain things that happened a decade ago with rare disease pricing. There was like a reaction to carriers. But it all normalized again. I think if people are saying there's real solutions that are needed, this is not what's changing. GLP-1 is like dramatically changing how they underwrite their ability to cover medicines for employers. But rare disease is not changing that equation for them. And so there's a lot more understanding of how to think about cell and gene therapies in the U.S. and the support. I think in Europe, they're still figuring it out. I think the systems are all very customized to each country. They all have their own processes. Things don't move as fast as some other countries. But again, there's an appreciation for medicines like CASGEVY, as evidenced by the early access in France, for instance. So I think you're going to there's just maybe a little timeline, but it's going to get sorted out. And I think the rest of the world, there's enough burden. And there's significant economic growth in other parts of the world that are non-U.S., non-Europe, where the markets have become more attractive now. And there's enough patients that you have to take those markets very seriously. So I think that's the great part about having Vertex as a partner that has global presence, the ability to move in different geographies, but also incredible experience with dealing with European payers. So I think not foreshadowing anything, and Vertex will guide. But I feel good from where I'm looking at things. Any thoughts on how patients may be opting or physicians opting for gene editing versus a gene therapy in this marketplace? Yeah. I think it's hard to handicap that right now because what's happened is not every site has both offerings. So to get a truly controlled experiment, you have to have a site that's offering both without any investigator or the physician bias to say, what are patients picking at the end of the day? But what I heard from one of the nonprofits that supports these patients that we help is, overwhelmingly, if they're given both options, they're going to choose a CRISPR-based option. It's just for it's hard to explain, but it's just easier for patients to understand. They say, I understand this notion of editing my gene. And I've read about CRISPR. I've seen an NPR article, X, Y, or Z. And this seems like the way to go for me. I don't think they understand lentiviral risks of AML or MDS. Those are all things that the patients don't fully understand or appreciate. They don't know how to think about it. But simplistically, I think what you're going to see is a majority of these patients just opt for CRISPR if both options are available. With regard to optimization going forward, I think currently it could take up to 5-6 months to get treated with CASGEVY. In addition, you've got this busulfan preconditioning regimen. There's potentially a path to get to a more benign preconditioning regimen. Where do you stand with both of those efforts? Yeah. I think the way I imagine the life cycle for CASGEVY is that at some point, a targeted conditioning agent is going to become a reality. And that's going to expand the addressable patient population significantly, 3-4x, perhaps. But it's not easy to bring that in a commercial setting. We still have a lot of work to do. But for both Vertex and us, this is a high priority. They have multiple agents that they're progressing forward with different targets. We have a secret antibody that we acquired from a company called Magenta. And we put a different toxin on it to develop it specifically for sickle cell and thalassemia, where we want the agent to be relatively safe. So the toxin is not as toxic as you might in the oncology settings. We want a very short half-life where it disappears before we put our cells in that are edited cells. So what that gives you are multiple reasonable shots to get a target conditioning in play. But once we've established the market, established the infrastructure to get Casgevy to as many patients as we can. So it's going to significantly increase the value of Casgevy if we get a conditioning that can show chimerism even in NHP. So let's see where the data land. But this is a high focus for us. The other part that we're working on, the 10-year solution, is in vivo editing for whether it's the bone marrow or any of the hematopoietic cells. It's more complex than most people imagine right now. I think you're going to see upstarts saying, oh, we've figured out HSC editing. The thing is, you have to do HSC editing without editing everything else at doses that are tolerable that also ensure durability. And they've edited the right type cell types. With that said, I think we are trying a number of targeted LNPs where we decorate the LNPs with different factors that may give us this preferential selective editing. And so that is an effort that we're putting a lot of resources behind. It just takes time. But that's sort of the 5- and 10-year horizon, if I think about what may happen with an autologous cell therapy associated with sickle cell and thalassemia. On the in vivo platform that you commented on earlier, we're going to see, I believe, first data this year in cardiovascular disease. Could you just frame that for us, how to think about this first data set and what would be meaningful? Yeah. We haven't guided to a time point for data yet, but we are accruing data. We have two trials ongoing for two cardiovascular risk factors that are well described in literature. One is Lp(a), and the second is ANGPTL3. They both are independent risk factors. Lp(a), for instance, we just looked at the number of cases where people have high Lp(a). It's not patients. It's people. Some of them are in their 30s and 40s, and they get heart attacks. Even though they're very healthy in their lifestyle, they exercise because they have significantly high Lp(a). It's kind of genetic in a way. What's been shown across all these population studies is lower Lp(a) is better. You have lower risk of cardiac events. What hasn't been shown yet is whether pharmacological intervention, which reduces Lp(a), then changes outcomes for people who are born with high or low Lp(a). And we're going to get that answer in the next 18 months, hopefully, or next year with the trials that Novartis and Amgen are running with ASOs and siRNAs, respectively. And so if you can show that pharmacological correlation of reducing Lp(a) with better outcomes, we're starting off at a very different point in our development journey where those parameters have been established. And we can then say, why not do this with gene editing, which is a much better way of reducing this risk factor in a sustained fashion versus the sawtooth effect that you may get with an ASO or siRNA, combined with the convenience of a one-time dosing. And so we're quite excited about those trials. I think as we dose patients and collect data, we'll see what dose level we need to get to, what the therapeutic index is. But a lot of what we're doing is very similar to what Intellia did with HAE and TTR. So we'll see where our data land. But that's going to be a signal for us where if the data are positive, one, we're very excited about these indications. But we're also going to really turbocharge six other indications where we're going to use the same LNP platform. You also have an emerging autoimmune vertical, and you're evaluating a drug in lupus. Perhaps talk to us, just given now how many assets are kind of entering the space in cell therapy, how you could be differentiated. And secondly, are you going to be able to take all these assets forward on your own, or are you thinking about partnerships going forward? Yeah, absolutely. I think while we see many cycles with investors and biotech ebbs and flows, there are these moments in time when you first describe certain data. I remember when the Emily Whitehead data, Carl June presented Emily Whitehead's case study. And it just changed how people thought about cell therapies in oncology. And this was, Emily Whitehead was like four or five years at the time. And she was cured of a terrible leukemia. And so the same sort of thing is happening with the Georg Schett data in, for cell therapies in autoimmune. You've had patients with very severe autoimmune diseases that are completely in remission and durably with a single administration of cell therapies, in this case, CD19 cell therapy. So it just opens up an opportunity that's even larger than oncology, with an opportunity to address, bring something to these patients who haven't had a solution for a long time. I think we've all seen these TV shows where lupus is the underlying cause of everything that happens. And it actually is a very complex disease. You get all these cerebral symptoms. You get neuropathic pain. You get, obviously, kidney issues and everything else. And if you can have a CD19-directed cell therapy that's potent, that gives you deep B-cell depletion, I think it can be transformative. Now, the question is, there's like 20 agents in the space. There's autologous CAR-Ts going into it. There's T-cell engagers, antibodies now, potentially ADCs. And then you have allogeneic cell therapies, both T-allo-CAR-Ts and allo-NKs. So what's going to win? I think this is why we are positioned to win this space. This is sort of all these factors coming together that we couldn't imagine. We were looking at it saying, gosh, this is sitting there for us to win in this space. The reason is the burden of B-cells you're going after is not as high as oncology. With an allo-CAR-T, you can get full B-cell depletion. Cell therapies go and deplete B-cells with the tissue resident B-cells that bispecifics and antibodies may not be able to. From a safety standpoint, the safety bar is high in autoimmune. You may not want to take any secondary malignancy risk that you may get with lentiviral-derived auto-CAR-T. Allo-CAR-T is better where it's CRISPR-edited and much more directed insertion of the CAR. The safety profile from a CRS and ICANS standpoint also is better for allo-CAR-T. Allo-CAR-Ts are better than allo-NK cells from a dosing standpoint and the ability to reduce COGS to a level that's meaningful commercially. We, as a company, have the best allo-CAR-T with a commercial-ready manufacturing facility, the lowest COGS out there, and the ability to create hundreds of doses available for trials that others don't. For all those reasons, I think we've been handed this opportunity where we want to take full advantage of it. We just announced the hiring of our Chief Medical Officer, Naimish Patel, who came from Sanofi. He was leading their entire autoimmune franchise there and developed Dupixent from the early days with incredible experience in the autoimmune space. We built a team around him to help with autoimmune. This is very high priority for us. We're moving as fast as we can. It helps that we have a strong balance sheet to support all the things we need to do to put us in pole position. Will you take all these programs forward? Yeah. I mean, we have that flexibility. The interesting thing, we have that flexibility. Given what we believe about Casgevy and the outlook, we have the flexibility to take both autoimmune and the in vivo programs forward ourselves all the way. Now, does that mean that we're not active on the BD front? I mean, I would say at J.P. Morgan this year, we had interest from at least half the top 20 pharma companies in these two programs, Lp(a) and autoimmune CAR-T. And so we'll continue talking to pharma companies because we don't want to turn a blind eye to that. But we're not going to partner both. At best, we partner one or the other. But there is the option to take both forward ourselves, which could create tremendous enterprise value for us in the near term as we get to hPOC. I want to get over to the oncology portfolio because that's one of the verticals you started with. You've been optimizing along the way. We're potentially going to see some data this year. Maybe walk us through what we could see from that effort and where you stand with the next generation assets. Yeah. We're glad that we're making a very persistent effort in oncology because it does take the next generation to get there. When we started the first generation CAR-T and CD19, CTX110, it was incredible to us that you're getting durable responses. Some of the patients that had complete responses with CTX110 are cancer-free 3 years out. The gold standard for oncology to be disease-free is 5 years. And I'm sure we're going to get there with patients who had the original complete response with a single dose of an unoptimized Allo-CAR-T that we created using CRISPR. Now we have CTX112, which is much more sophisticated. And we've made these edits to make them that much more potent, yet retain the safety features. With DLBCL, while the landscape has changed a lot, there are a few things that have emerged now, which is T-cell engagers are not as good from a durability standpoint as people originally imagined them to be. When people looked at 9 cycles of glofitamab, whatever you said, gosh, at 15 months, looks like everybody's still in CR. So this could be the same thing that we're seeing with Yescarta, perhaps, where if people are in CR 1 year, they're probably in CR 2 years. And that hasn't been the case. They've lost nearly half the CRs between year 1 and year 2. And you're seeing that in the marketplace. You're not seeing bispecifics all of a sudden have a huge sales trajectory that people anticipated because of this durability reason. And the real-world data on CRs is also lower than what people saw in the clinical trials. With autologous CAR-T, you still have a very high bar to beat. But what's also happened is only about 25% of patients that are eligible or should benefit from this therapy are getting it because it's basically saturated all the academic medical centers. And all the community practices don't know how to deal with it yet. And they never will. This is too complex for them. There is reimbursement risk. There is inventory risk. There is risk of CRS and not being able to deal with that with the patient. So it's never going to get to that population. And the only way to get to that 75% of the population is to have allogeneic CAR-Ts with that durability. And so we'll have data this year in DLBCL. We've seen some other data sets recently from other allo-CAR-Ts. But we'll have our own data set. You may not get the whole durability answer at this point. You'll get a good indication of which way it's trending based on at least comparisons of 110 to 112 or what you're seeing with this patient population. We'll have data later this year that informs not only our oncology path forward but may also read through to autoimmune. Just remind us the targets here. We'll see CD19 and BCMA? Well, CD19. CD70 is the other program that we're advancing right now in solid tumors and in heme malignancies. We haven't said when we're going to have the data for that yet. But with CTX130, which was a CD70-targeted allo-CAR-T in heme malignancies in T-cell lymphomas, we already saw data that was a product. We saw CRs in patients that had no hope. In fact, one of the patients was the subject of an NPR article where it was a former NBA player who couldn't walk because they were wheelchair-bound because they had lymphoma all over their feet and all over his skin. And a month later, dancing around, walking around, running. And you've had these cases in these very difficult-to-treat lymphomas. And CTX131 gives us that much better opportunity to treat these patients, get more patients in CR, and complete remissions. Some of the patients, we actually want to get into CR and go on to get an allotransplant, which is actually the best outcome they can get. We'll have multiple data sets in addition to solid tumors that inform our general cancer franchise strategy later this year. Maybe just to round out here, the regenerative medicine vertical, how much are you prioritizing that effort with type 1 diabetes or anything else? Yeah, it's a significant priority. Again, we have to make bets while others may be written it off or saying it's too difficult because that's how we're going to create alpha. That's how we're going to create tremendous value. And what you're seeing is we're already seeing a lot of benefit with the beta-2 microglobulin with our cancer programs. We've made other edits like HLA-E knock-in. We've made edits like PD-L1 knock-in to make cells stealth. And if we crack the nut on making these cells stealth, it opens up the possibilities not just for type 1 diabetes but for many other organ systems. I mean, you can imagine now stories where people are creating mini pig kidneys for human transplantation. They will all need the same edits around making them stealth. You're seeing islet cells is the best place to start because that's the best controlled experiment to see if these cells truly are stealth. And now we have both a device approach and a device-free approach that we're developing ultimately that's going to inform us on not just the stealth nature but are we getting enough efficacy from an insulin production standpoint in a glucose-responsive fashion with these cells that allows the dose titrate. So the last part of this is now that we have the program back from Vertex, we're now doing all the development and manufacturing ourselves. Once we can do the manufacturing ourselves, it gives us tremendous flexibility to have multiple generations of products and move them all into clinic and parallel process different T-cells at the same time. With that, Sam, thank you so much. Really enjoyed the discussion. Thank you very much.